Cancer is one of the main diseases of the 21st century causing 13% of all deaths. New aspects of the genetics of cancer pathogenesis, such as DNA methylation are increasingly recognized as important. While there are several chemicals that can affect rapidly dividing cancer cells most of these are toxic with adverse side effects. Chemo-resistance to many of these drugs leads to relapse of patients often exhibiting more aggressive cancer progression, with little or no alternative treatments available. New diagnostics', prognostics' and treatments' are needed.
Despite numerous advances in our knowledge of cancer, our ability to develop clinically effective therapies based on this understanding has met with limited success. Current therapies can control tumor growth initially, but most patients ultimately relapse. One prominent example is lung cancer, the leading cause of cancer-related mortality with over 1 million deaths each year. NSCLC accounts for approximately 85% of all lung cancers. Although NSCLC patients with EGFR mutations respond to EGFR inhibitors initially, most patients experience a relapse within 1 year. These findings underscore the urgent need for both combination therapies and also new approaches to treat cancerous tumors. Lung cancer is a devastating disease and a major therapeutic burden with poor prognosis. The functional heterogeneity of lung cancer is highly related with clinical chemo-resistance and relapse.
Data from leukemias, germ cell tumors and a number of solid tumors support the notion that cancers are maintained by a subpopulation of self-renewing and evolving tumor initiating cells (TICs). This is also popularly known as the cancer stem cell (CSC) model. Although the validity of the CSC model is an issue of controversy in melanoma, many other solid tumors appear to follow the CSC model. Recently it was proposed that at earlier stages of tumorigenesis, rare TIC clones differentiate into non-malignant progeny to form the bulk of the tumor, while at advanced stages TIC clones constitute the bulk of the tumor. Studies have also begun to reconcile the connection between the evolving genotype of TIC clones and the surface phenotype of TICs, using mouse models of lung cancer such as those described in WO 2010/126452. Thus accumulated findings suggest that targeting TICs may be a promising approach for eradicating tumors early. However progress in the targeting of TICs to improve cancer therapy has been hindered by a lack of understanding of the molecular pathways that are critical to TICs.
Recent studies have led to an emerging appreciation of the importance of metabolic reprogramming in cancer and a resurgence of interest in the Warburg effect—the phenomenon whereby cancer cells, like embryonic cells, preferentially use glycolysis even under aerobic conditions (Warburg, 1956. Origin of cancer cells. Science 123, 309-314).
Glycine dehydrogenase (decarboxylating) (GLDC) is an enzyme belonging to the family of oxidoreductases, specifically those acting on the CH—NH2 group of donors with a disulfide as acceptor. This enzyme participates in glycine, serine and threonine metabolism. It employs pyridoxal phosphate as a cofactor. GLDC is one of four proteins that form the glycine cleavage system in all eukaryotes which catalyzes the degradation of glycine. High levels of glycine in humans or glycine build up is known to glycine encephalopathy.